As neoadjuvant enfortumab vedotin plus pembrolizumab (EVP) achieves high pathologic complete response rates in MIBC, a critical question emerges: is adjuvant EVP necessary for everyone? Continuing treatment in patients who are already cancer-free post-surgery may offer no extra benefit while increasing toxicity.

Unlike traditional chemotherapy, the EV+pembrolizumab combination is producing a "tail on the curve" in survival data. This indicates a significant minority of patients with metastatic bladder cancer are achieving durable, long-term responses—a phenomenon previously unseen and a paradigm shift for the disease.

The transformative efficacy of EV-Pembro has ushered in a new, aggressive treatment philosophy for both muscle-invasive and metastatic bladder cancer. The approach is to administer the combination upfront to gain rapid disease control, and only then make subsequent decisions about surgery, radiation, or further therapy.

Despite the perception that cisplatin-ineligible patients have worse disease biology, the pathologic complete response rates to neoadjuvant EV Pembro were nearly identical (56-57%) in both cis-ineligible (KEYNOTE-905) and cis-eligible (KEYNOTE-B15) trials. This suggests the regimen's high efficacy may overcome underlying biological differences.

Remarkable pathologic response rates from just 3-4 cycles of neoadjuvant EV-Pembro are creating divergent research questions. Future trials will explore whether some patients could benefit from more cycles (escalation) while high-responders might be able to skip cystectomy entirely (de-escalation).

In cisplatin-ineligible muscle-invasive bladder cancer, neoadjuvant enfortumab vedotin plus pembrolizumab demonstrated a 57% pathologic complete response rate in the KEYNOTE-905 trial. This is an unprecedented result, significantly higher than any previously studied regimen and signals a major shift in perioperative treatment.

Professor Powles predicts a significant shift in bladder cancer treatment. High pathological complete response rates with neoadjuvant EV Pembro may allow responders, identified by imaging and circulating tumor DNA, to safely avoid radical cystectomy, a life-altering surgery that may become unnecessary for many.

The success of new treatments like immunotherapy and ADCs leads to more patients achieving a deep response. This high efficacy makes patients question the necessity of a radical cystectomy, a life-altering surgery, creating an urgent need for data-driven, bladder-sparing protocols.

With pathologic complete response rates approaching 67% in patients completing neoadjuvant EV-Pembro, a majority of cystectomies are now removing cancer-free bladders. This creates an ethical and clinical imperative to rapidly launch prospective trials to validate bladder preservation strategies and avoid overtreatment.